Dopamine Agonists are commonly used in the treatment of Parkinson's disease; however, their use can be limited by adverse events with various levels of severity. The initiation of dopamine agonists are typically associated with nausea, vomiting and orthostatic hypotension. These side effects are more pronounced with higher doses but can usually be mitigated with a slow and complex titration schedule. Pramipexole (as well as several other DA agonists) is also associated with impulse control disorders, peripheral edema, psychosis, and sedation, that can be difficult to control and therefore limit the utility of this medication. rasagiline, another drug used in the treatment of Parkinson's disease, is largely well tolerated but also has some safety concerns particularly with respect to the risk of a cheese reaction (hypertensive crisis) with foods that are high in tyramine and a serotonin reaction (excess serotonin activity) when employed in combination with selective serotonin reuptake inhibitors and other anti-depressants that are commonly prescribed in Parkinson's disease. Among both drugs higher doses of pramipexole are typically associated with a greater risk of sever adverse effects and therefore it is important for clinicians to have treatment strategies that allow for the greatest efficacy in controlling PD symptoms, while minimizing motor complications and DA-induced adverse events.
Pharma Two B discovered that combining agents with complementary mechanisms of action (i.e., two different active agents having symptomatic or neuroprotective effects) allows for enhanced anti-Parkinsonian efficacy in comparison to what can be achieved with higher doses of either agent alone (WO2009147681). Preclinical data generated previously by Pharma Two B suggests that low doses of the MAO-B inhibitor rasagiline and the dopamine agonist pramipexole act synergistically in improving the effectiveness of these drugs. Given the relatively troublesome adverse event profile associated with initiating treatment with dopamine agonists, current treatments include a titration schedule of low doses, which are not expected to have therapeutic effect but to minimize the side effects caused by immediate start with effective doses. Moreover, undesirable effects are associated with long-term treatment with higher doses of the dopamine agonist. Thus, the option of using a combination containing low doses of dopamine agonist is favorable for many patients and may provide high therapeutic effect with minimal side effects.